A sphingolipid is a lipid having important roles within a living body. Various sphingolipids, having sphingosine as a constituent, are widely distributed within a living body, including within the nervous system on the surface cell membranes. Sphingosine is a compound having the chemical structure
wherein Y is hydrogen. Sphingolipids present on cell membranes function to regulate cell growth; participate in the development and differentiation of cells; function in nerves; are involved in the infection and malignancy of cells; and the like.
Many of the physiological roles of sphingolipids remain to be solved. However, it is known that lipidosis, for example, is caused by accumulation of a particular sphingolipid in the body. Further, it has recently been discovered that ceramide, a derivative of sphingosine, potentially has an important role in the mechanism of cell signal transduction, and studies about its effect on apoptosis and cell cycle have been reported.
Sphingosine-1-phosphate, for example, is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomyeline cycle (in animal cells). Sphingosine-1-phosphate has also been found in insects, yeasts and plants.
The enzyme, ceramidase, acts upon ceramides to release sphingosine, which is phosphorylated by sphingosine kinase, a ubiquitous enzyme in the cytosol and endoplasmic reticulum, to form sphingosine-1-phosphate. The reverse reaction can also occur by the action of sphingosine phosphatases, and the enzymes act in concert to control the cellular concentrations of sphingosine-1-phosphate. In plasma, sphingosine-1-phosphate concentrations can reach 0.2 to 0.9 μM, and is found in association with the lipoproteins, especially high density lipoproteins (HDL). It should also be noted that sphingosine-1-phosphate formation is an essential step in the catabolism of sphingoid bases.
Like its precursors, sphingosine-1-phosphate is a potent messenger molecule that perhaps uniquely operates both intra- and inter-cellularly, but with very different functions from ceramides and sphingosine. The balance between these various sphingolipid metabolites may be important for health. For example, within the cell, sphingosine-1-phosphate promotes cellular division (mitosis) as opposed to cell death (apoptosis), which it inhibits. Intracellularly, sphingosine-1-phosphate also functions to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli. It is suggested that the balance between sphingosine-1-phosphate and ceramide and/or sphingosine levels in cells is critical for their viability. In common with the lysophospholipids, especially lysophosphatidic acid, with which it has some structural similarities, sphingosine-1-phosphate exerts many of its extra-cellular effects through interaction with five specific G protein-coupled receptors on cell surfaces. These are important for the growth of new blood vessels, vascular maturation, cardiac development, cardiac immunity, and for directed cell movement.
Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism. Sphingosine-1 phosphate is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It might also play a critical role in platelet aggregation and thrombosis, and could aggravate cardiovascular disease. Alternatively, the relatively high concentration of the sphingosine-1 phosphate in HDL may have beneficial implications for atherogenesis. For example, there are recent suggestions that sphingosine-1-phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium. In addition, similar to lysophosphatidic acid, sphingosine-1 phosphate is a marker for certain types of cancer, and there is evidence that sphingosine-1 phosphate's role in cell division and proliferation may have an influence on the development of cancers. These are currently topics that are attracting great interest amongst medical researchers, and the potential for therapeutic intervention in sphingosine-1-phosphate metabolism is under active investigation.
Further, fungi and plants have sphingolipids and the major sphingosine contained in these organisms has the formula
These lipids have important roles in the cell growth of fungi and plants, but details of the roles remain to be solved.
Derivatives of sphingolipids and their related compounds exhibit a variety of biological activities through inhibition or stimulation of metabolic pathways. These compounds include inhibitors of protein kinase C, inducers of apoptosis, immuno-suppressive compounds, antifungal compounds, and the like. Substances having these biological activities can be useful compounds for treating various diseases.
Derivatives of sphingosine have been prepared in various patents. For example, see U.S. Pat. Nos. 4,952,683; 5,110,987; 6,235,912 and 6,239,297. Also, compounds which are similar to some sphingosine derivatives, but which are not reported as being ligands for the sphingosine receptors, are reported in various patents and published patent applications. See for example, U.S. Pat. Nos. 5,294,722; 5,102,901; 5,403,851 and 5,580,878, and U.S. Patent Application Publication No. U.S. 2003/0125371.